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Trial registered on ANZCTR


Registration number
ACTRN12618001747213
Ethics application status
Approved
Date submitted
19/10/2018
Date registered
24/10/2018
Date last updated
24/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of the non-nutritive bitter taste flavouring, denatonium benzoate (DB), and the low-nutritive bitter taste amino acid, leucine, on gastrointestinal hormone secretion and energy intake in health and type 2 diabetes – regional differences in small intestinal exposure.
Scientific title
Effects of the non-nutritive bitter taste flavouring, denatonium benzoate (DB), and the low-nutritive bitter taste amino acid, leucine, on gastrointestinal hormone secretion and energy intake in health and type 2 diabetes – regional differences in small intestinal exposure.
Secondary ID [1] 296377 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes mellitus 310118 0
obesity 310119 0
Condition category
Condition code
Metabolic and Endocrine 308868 308868 0 0
Diabetes
Metabolic and Endocrine 308869 308869 0 0
Normal metabolism and endocrine development and function
Diet and Nutrition 308870 308870 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Following enrolment, each subject will be studied on 5 occasions, separated by at least 7 days, in a double-blind, randomized fashion.
On each study day, a customised multi-lumen silicone catheter will be inserted through an anesthetized nostril and allowed to pass into the small intestine by peristalsis. The catheter will be positioned with the two infusion ports (i.e. proximal and distal small intestinal infusion ports) located at 13 cm (i.e. the duodenum) and 190 cm (i.e. the ileum) beyond the pylorus, respectively, while subjects laid in a supine position. An intravenous cannula will be placed into a vein on the dorsum of the hand, which will be kept warm with a heat pad to allow sampling of “arterialised” blood.
Once the intraluminal catheter is correctly positioned, one of the following 5 treatments will be administered:
(i) duodenal (150 mL 0.9% saline)+ ileal saline (150 mL 0.9% saline) (i.e. control)
(ii) duodenal DB (30mg dissolved in 0.9% saline to 150 mL)+ ileal saline (150 mL 0.9% saline) (i.e. duodenal DB)
(iii) duodenal saline (150 mL 0.9% saline) + ileal DB (30 mg, dissolved in 0.9% saline to 150 mL) (i.e. ileal DB)
(iv) duodenal leucine (5 g dissolved in 0.9% saline to 150 mL) + ileal saline (150 mL 0.9% saline) (i.e. duodenal leucine), and
(v) duodenal saline (150 mL 0.9% saline) + ileal leucine (5 g dissolved in 0.9% saline to 150 mL).
Each treatment will be administered during t = 0-60 min by one of the medically trained investigators. At t = 60 min, the catheter will be removed.
Intervention code [1] 312713 0
Treatment: Other
Comparator / control treatment
150 mL 0.9% saline infused into duodenum or ileum
Control group
Placebo

Outcomes
Primary outcome [1] 307841 0
differences in the incremental area under the curve (iAUC) for plasma GLP-1 between the treatments
Timepoint [1] 307841 0
t = 0, 15, 30, 45 and 60 min where t=0 is when infusion started.
Secondary outcome [1] 353103 0
differences in energy intake from a standardised cold buffet meal between the 5 treatments are assessed by weighing each food item before and after consumption. The amount of energy intake is calculated using Foodworks 3.01 (Xyris Software, Highgate Hill, QLD, Australia).
Timepoint [1] 353103 0
t= 90min where t=0 is when rectal infusion started.
Secondary outcome [2] 353104 0
differences in the incremental area under the curve (iAUC) for plasma PYY between the treatments
Timepoint [2] 353104 0
t = 0, 15, 30, 45 and 60 min where t=0 is when infusion started.
Secondary outcome [3] 353105 0
differences in the incremental area under the curve (iAUC) for glucose, assessed by plasma assay, between the treatments
Timepoint [3] 353105 0
t = 0, 15, 30, 45 and 60 min where t=0 is when infusion started.
Secondary outcome [4] 353106 0
differences in the incremental area under the curve (iAUC) for gastrointestinal sensations, assessed by validated visual analogue scales, between the 5 treatments.
Timepoint [4] 353106 0
t = 0, 15, 30, 45 and 60 min where t=0 is when infusion started.

Eligibility
Key inclusion criteria
Patients with type 2 diabetes (World Health Organisation (WHO) criteria), HbA1c less than or equal to 8.5%, managed by diet or metformin alone, body mass index 20-35 kg/m2, both males and females aged 18-75 years.

Healthy volunteers, matched as closely as possible to the diabetic subjects for age, sex, and BMI.

Additional inclusion criteria include: haemoglobin above the lower limit of the normal range (ie. more than 135g/L for men and 115g/L for women), and ferritin above the lower limit of normal (ie. more than 30ng/mL for men and more than 20mg/mL for women)
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Use of any medication that may influence gastrointestinal motor function, body weight or appetite (e.g. antihypertensive drugs, domperidone and cisapride, anticholinergic drugs (e.g. atropine), metoclopramide, erythromycin, hyoscine, orlistat, green tea extracts, Astragalus, St. John's Wort etc.)
Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes on a daily basis
History of gastrointestinal disease, including significant upper or lower gastrointestinal symptoms, pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendicectomy or cholecystectomy)
Other significant illness, including epilepsy, cardiovascular or respiratory disease
Impaired renal or liver function (as assessed by calculated creatinine clearance < 90 mL/min or abnormal liver function tests (> 2 times upper limit of normal range))
Donation of blood within the previous 3 months
Participation in any other research studies within the previous 3 months
Inability to give informed consent
Female participants who are pregnant or planning for pregnancy, or are lactating
Vegetarians

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Based on data derived from our previous study, 16 healthy and 16 T2DM subjects will provide 80% power (at a=0.008, to allow for corrections of 6 subgroup comparisons: duodenal DB vs. placebo; ileal DB vs. placebo; duodenal DB vs. ileal DB; duodenal leucine vs. placebo; ileal leucine vs. placebo; duodenal leucine vs. ileal leucine) to detect a difference of 660 pmol/L*min in the 60-min incremental area under the curve (iAUC) for plasma GLP-1 between the treatments. 20 subjects for each group will be recruited to allow for dropouts.
Data will be analysed using standardised, non-parametric or parametric statistical methods where appropriate (e.g. repeated measures ANOVA).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/11/2018
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 300980 0
Government body
Name [1] 300980 0
NHMRC
Country [1] 300980 0
Australia
Primary sponsor type
University
Name
University of Adelaide
Address
Level 5 Adelaide Health and Medical Sciences (AHMS) Building,
North Terrace
Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 300564 0
None
Name [1] 300564 0
Address [1] 300564 0
Country [1] 300564 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301741 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 301741 0
Level 3, Roma Mitchell House
136 North Terrace, Adelaide, South Australia, 5000
Ethics committee country [1] 301741 0
Australia
Date submitted for ethics approval [1] 301741 0
31/07/2018
Approval date [1] 301741 0
29/09/2018
Ethics approval number [1] 301741 0
R20180816

Summary
Brief summary
Emerging evidence of preclinical studies suggests that bitter substances in the gut can reduce appetite and slow the emptying of meals from the stomach, by stimulating GI hormone release. The purpose of this study is to determine the importance of the region of small intestine exposed, and the role of bitter taste signalling, to the release of GI hormones and energy intake responses in both health and T2DM. we wish to investigate whether the non-nutritive bitter taste flavouring, denatonium benzoate (DB), and the low-nutritive bitter taste amino acid, leucine, induce substantially more glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion when infused into the ileum than the duodenum, associated with greater suppression on energy intake in both healthy subjects and patients with T2DM.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87958 0
Dr Tongzhi Wu
Address 87958 0
University of Adelaide Discipline of Medicine, Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace, Adelaide, SA 5000
Country 87958 0
Australia
Phone 87958 0
+61 883136535
Fax 87958 0
Email 87958 0
[email protected]
Contact person for public queries
Name 87959 0
Tongzhi Wu
Address 87959 0
University of Adelaide Discipline of Medicine, Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace, Adelaide, SA 5000
Country 87959 0
Australia
Phone 87959 0
+61 883136535
Fax 87959 0
Email 87959 0
[email protected]
Contact person for scientific queries
Name 87960 0
Tongzhi Wu
Address 87960 0
University of Adelaide Discipline of Medicine, Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace, Adelaide, SA 5000
Country 87960 0
Australia
Phone 87960 0
+61 883136535
Fax 87960 0
Email 87960 0
[email protected]

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No Supporting Document Provided



Results publications and other study-related documents

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